Know the enemy and know yourself: Addressing cryptic fungal pathogens of humans and beyond

If you know the enemy and know yourself, you need not fear the result of a hundred battles.If you know yourself but not the enemy, for every victory gained you will also suffer a defeat.If you know neither the enemy nor yourself, you will succumb in every battle."-SunTzu, The Art of War Fungal pathogens threaten human welfare, including human and animal health and global food security.For example, ameliorating crop loss due to fungal plant pathogens would feed nearly 600 million more people [1].Fungal infections of humans are difficult to diagnose and treat, potentially leading to serious illness and death, especially in immunocompromised individuals; case in point, there are an estimated 1.7 million deaths per year and more than 150 million severe fungal infections worldwide [2].These issues may be exacerbated due to climate change.Reflecting the importance of combatting and preventing infection diseases caused by fungi, the World Health Organization recently released a list of priority fungal pathogens (https://www.who.int/publications/i/item/9789240060241).Accordingly, fungi that cause disease have become a major research focus, resulting in a deeper, but still incomplete, understanding of virulence and the cadre of pathogenic species.Most human fungal pathogens are opportunistic and affect immunocompromised individuals.This suggests that any fungus capable of growing in the human body and overcoming or evading a compromised immune system could cause disease.Supporting this notion, advances in DNA sequencing of clinical isolates have led to the realization that cryptic fungal speciesmorphologically indistinguishable from known pathogens but genetically distinct-are an underappreciated source of infections [3-6].Cryptic species have been identified in several fungal genera of agricultural and biomedical significance, such as plant pathogens (e.g., Fusarium) [7] and human pathogens (e.g., Aspergillus; Table 1) [3].Due to morphological similarities (Fig 1), cryptic fungi are difficult to diagnose using typical microbiology techniques in the clinical setting, resulting in an incomplete understanding of their epidemiology and clinical burden.Here, major research avenues that aim to enrich our understanding of cryptic fungal pathogens-as well as other major pathogens-and diminish their impact on human welfare are discussed.Cryptic fungal pathogens from the genus Aspergillus are used as an example.We argue that the impact of fungal infections, especially among cryptic species for which little is known, can be reduced if we have an in-depth understanding of pathogens, humans, and the interaction between the two.